Cell specific Partitioning Defective Par1a/b deletion effects on renal repair

细胞特异性分区缺陷 Par1a/b 缺失对肾修复的影响

基本信息

批准号：
10528487
负责人：
Kimberly Jean Reidy
金额：
$ 44.7万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10528487
关键词：
Ablation Activities of Daily Living Acute Acute Renal Failure with Renal Papillary Necrosis Adult Cell Cycle Cell Differentiation process Cells Chronic Chronic Kidney Failure Clinical Compensation Data Development Dialysis procedure Disease Progression Epithelial Cells Epithelium Family Fibrosis Folic Acid Gene Expression Goals Human Impairment Infiltration Inflammatory Injections Injury Injury to Kidney Kidney Kidney Diseases Knowledge Laboratories Link LoxP-flanked allele Membrane Modeling Mus Myofibroblast Notch Signaling Pathway Pathway interactions Persons Phosphotransferases Population Proliferating Protein Family Protein-Serine-Threonine Kinases Recovery Regulation Renal function Renal tubule structure Reperfusion Injury Role Signal Pathway Signal Transduction Testing Tetanus Helper Peptide Time Tubular formation Up-Regulation Ureteral obstruction WNT Signaling Pathway epithelial stem cell human disease in vivo inhibitor innovation insight interstitial kidney fibrosis kidney repair knock-down loss of function member mouse model new therapeutic target notch protein novel pharmacologic prevent repaired response single-cell RNA sequencing stem cell proliferation stem cells synergism targeted treatment therapeutic target tool

项目摘要

Abstract We will study the role of serine threonine kinases Partitioning defective (Par) 1a and 1b in adaptive and maladaptive repair following tubular injury. In studies by our laboratory of the developing kidney, dual loss of Par1a and 1b impaired Notch activation: this demonstrated for the first time a link between Par1 and Notch signaling. We hypothesize: Par1a/b kinases are activated in proliferating progenitor cells by kidney injury and regulate Jag1-Notch dependent and independent pro-fibrotic pathways. Using inducible cell specific deletion of both Par1a/b in mice, we will test effect of Par1a/b on Notch activation and progenitor cells following injury. We will investigate the mechanisms underlying the novel Par1-Notch link. Our specific aims are: 1) Show that Par1a/b regulates the response to kidney tubule injury via the Notch pathway; and 2) Demonstrate that Par1a/b in tubular progenitor cells promotes maladaptive repair.

抽象的我们将研究丝氨酸苏氨酸激酶分配有缺陷（PAR）1a和1b的作用管状损伤后自适应和不良适应性修复。在我们的实验室研究中开发肾脏，par1a的双重损失和1B的障碍障碍激活：这证明了 PAR1和Notch信令之间的第一次链接。我们假设：par1a/b激酶是通过肾脏损伤激活祖细胞并调节Jag1-依赖性和独立的促纤维途径。使用par1a/b的诱导型细胞特异性缺失小鼠，我们将测试par1a/b受伤后的牙齿激活和祖细胞的作用。我们将研究新型PAR1-NOTCH链接的基础机制。我们的具体目的是：1）证明PAR1A/B通过Notch途径调节对肾小管损伤的反应；和2）证明管状祖细胞中的par1a/b会促进适应不良的修复。